The instant invention is directed to glucocorticoid receptor-selective antagonists which are useful for treating type II diabetes, obesity, hyperglycemia, inadequate glucose clearance, hyperinsulinemia, hypertriglyceridemia, and high-circulating glucocorticoid levels, preparations of the compounds, compositions containing the compounds, and methods of treatment using the compounds.
Non insulin-dependent diabetes mellitus (type II diabetes), a debilitating disease characterized by abnormal elevation of blood glucose levels, is driven by three factors: increased hepatic glucose production, inadequate clearance of glucose via insulin mediated pathways, and decreased uptake of circulating glucose by tissues. (Diabetes Review 5(3), 177-269, (1997)). Administration of agents which decrease hepatic glucose production are a fundamental approach to controlling blood glucose levels (Am. J. Physiol. 257, E35-E42 (1989). J. Clin. Endocrinol. Metab. 77, 1180-1183 (1994) and J. Clin. Invest., 92, 2283-2290 (1993)).
Glucocorticoids have been shown to have major influences on glucose production.
Glucocorticoid excess aggravates established diabetes and glucocorticoid deficiency reduces blood glucose and improves glucose control in diabetic mice. (Diabetes Review, 1(3), 301-308, (1993). Diabetologia, 9, 376-379 (1973). Horm. Metab. Res., 9, 152-156 (1977)). The underlying mechanism responsible for these effects is believed to be glucocorticoid-induced upregulation of hepatic enzymes required for gluconeogenesis. (Recent Prog. Horm. Res., 26, 411-457 (1970). Physiol. Rev., 64, 170-259 (1984).
The glucocorticoids are lipid soluble hormones synthesized in the adrenal cortex. They readily pass through cell membranes, enter the cytoplasm of target tissues, and bind to glucocorticoid receptors in the cytoplasm by complexation with heat shock proteins. Upon binding of the hormone to its receptor, the receptor undergoes a conformational change which results in dissociation of heat shock proteins and translocation of the ligand-bound glucocorticoid receptor into the nucleus where it can either initiate or repress specific gene transcription. Transcriptional activation occurs when the ligand bound receptor complex homodimerizes, and the homodimeric receptor ligand complex binds to chromosomal DNA at sequence-specific sites in the promoter region of regulated genes. (Cell, 56, 335-344 (1989). Annu. Rev. Genet., 19, 209-215 (1989)). Among the genes which glucocorticoids up-regulate are those which play key roles in gluconeogenesis and glycogenolysis, particularly PEPCK and glucose-6-phosphatase. (Advanced Enzymology., Meister, Ed. New York, John Wiley and Sons, Inc., 203-281 (1994). and Diabetes 45, 1563-1571(1996)).
Phosphoenolpyruvatecarboxy kinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate into glucose, both of which are required for the synthesis of glucose from oxaloacetate in the liver. Recently, it has been shown that Aventis(copyright) (mifepristone), a potent glucocorticoid receptor (GR) antagonist, reduces mRNA levels of PEPCK and glucose-6-phosphate in the liver and causes a 50% reduction of plasma glucose levels in obese diabetic db/db transgenic mice. (J. Biol. Chem. 272(50), 31475-31481 (1997)). While steroid-based GR antagonists have been useful in demonstrating efficacy for in vivo glucose lowering effects, the utility of such agents is limited due to side effects resulting from potent cross-reactivity with other steroid receptors, in particular progesterone receptor (PR) and mineralocorticoid receptor (MR).
Because agents which function as glucocorticoid antagonists represent a novel approach to controlling type II diabetes, agents which antagonize the glucocorticoid receptor have been the subject of active current research for their clinical potential. Reference is made to U.S. Pat. No. 5,929,058, which discloses a method for treating type II diabetes comprising administering a combination of nonselective steroidal agents exhibiting mineralcorticoid receptor agonist activity and glucocorticoid receptor antagonist activity.
Thus, it would be an important contribution to the art to provide non-steroidal, glucocorticoid-selective agents which antagonize the glucocorticoid receptor. These compounds would be particularly useful for treating type II diabetes and the symptoms thereof, such as hyperglycemia, inadequate glucose clearance, obesity, hyperinsulinemia, hypertriglyceridemia, and high circulating glucocorticoid levels.
In its principle embodiment, therefore, the instant invention is directed to compounds which are useful for treating type II diabetes, obesity, hyperglycemia, inadequate glucose clearance, hyperinsulinemia, hypertriglyceridemia, and high-circulating glucocorticoid levels, said compounds having formula I 
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R1 is selected from the group consisting of
(1) alkanoyl, cyano, halo, hydroxy;
(2) alkyl, alkenyl, alkynyl, alkoxy, alkanoyloxy;
wherein each group defining (2) can be optionally substituted with 1-4 substituents independently selected from alkoxy, alkoxycarbonyl, amino, carboxamido, cyano, halo, hydroxy, oxo, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;
wherein the substituted aryl, substituted heteroaryl, and substituted heterocyclyl groups are substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, perfluoroalkyl, and perfluoroalkoxy;
(3) cycloalkyl, aryl, heteroaryl, heterocyclyl;
wherein each group defining (3) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, oxo, perfluoroalkyl, and perfluoroalkoxy;
(4) CO2R12, OR12, SR12, S(O)R12, and SO2R12;
wherein R12 is selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
wherein each group can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkoxyalkoxy, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy;
R2 is selected from hydrogen and R1; or
R1 and R2 together are xe2x80x94X1xe2x80x94Y1xe2x80x94Z1xe2x80x94, wherein X1 is selected from a covalent bond, O and CH2; Y1 is selected from C(O), alkylene, and alkenylene; and Z1 is selected from CH2, CH2O, CH2NR13, NR13, and O;
wherein R13 is selected from
(1) hydrogen
(2) alkyl,
wherein the alkyl can be optionally substituted with 1-4 substituents independently selected from alkenyl, alkoxy, cycloalkyl, aryl, and halo, and
(3) aryl;
R3, R4, R7, R8, and R9 are independently selected from hydrogen and R1;
L is selected from a covalent bond and alkylene;
R5 is selected from
(1) alkanoyl, alkoxy, alkenyloxy, alkynyloxy, alkoxycarbonyl, cyano;
(2) aryl, arylalkyl, heteroaryl, and heterocyclyl,
wherein each group defining (2) can be optionally substituted with 1-5 substituents independently selected from alkanoylamino, alkanoylaryloxy, alkyl, alkylsulfonamido, alkenyl, alkenyloxy, alkynyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxyaryl, alkoxycarbonyl, alkoxycarbonyalkyl, alkoxycarbonylalkenyloxy, amino, aminoalkyl, aminoaryl, aryl, arylalkyl, arylalkenyl, arylalkynyl, aryloxy, arylsulfonamido, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, carboxyaryl, cyano, cyanoalkyl, heteroaryl, (heteroaryl)heteroarylsulfonamido, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, hydroxyalkynyl, halo, haloalkyl, haloalkylsulfonamido, nitro, oxo, perfluoroalkyl, perfluoroalkoxy and trialkylsilylalkyl;
(3) alkyl, alkenyl, alkynyl, cycloalkyl,
wherein each group defining (3) can be optionally substituted with 1-4 substituents independently selected from alkoxy, alkenyloxy, alkoxycarbonyl, amino, aryl, carboxamido, carboxy, cyano, halo, hydroxy, and oxo;
R6 is selected from hydrogen and alkyl; or
-L-R5 and R6 together are selected from 
wherein d is 1-4 and A is selected from CH2, O, S, SO2, and NR13 and 
wherein the carbonxe2x80x94carbon double bond of (2) can be in the E or Z configuration and R26 selected from
(1) alkyl,
wherein the alkyl can be optionally substituted with 1-4 substituents independently selected from alkenyl, alkynyl, alkoxy, alkoxycarbonyl, amino, aryl, carboxamido, carboxy, cyano, heteroaryl, heterocyclyl, hydroxy, and halo;
(2) aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each group defining (2) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy;
R10 and R11 are independently selected from
(1) hydrogen,
(2) alkyl,
wherein the alkyl can be optionally substituted with 1-4 substituents independently selected from (a) alkenyl, (b) alkynyl, (c) alkoxy, (d) aryl, (e) cycloalkyl, (f) heteroaryl, (g) heterocyclyl, (h) alkoxycarbonyl, (i) carboxy, and (j) halo;
wherein (a)-(c) can be optionally substituted with 1-4 substituents independently selected from aryl, alkoxy, cycloalkyl, heteroaryl, heterocyclyl, alkoxycarbonyl, carboxy, and halo; and
wherein (d)-(g) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy;
(3) aryl, cycloalkyl, heteroaryl, heterocyclyl;
wherein each group defining (3) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy;
(4) xe2x80x94SO2R35 and xe2x80x94C(O)R36;
wherein R35 and R36 are independently selected from
(a) alkoxy, amino,
(b) alkyl, alkenyl,
wherein each group defining (b) can be optionally substituted with 1-4 substituents independently selected from (i) alkenyl, (ii) alkynyl, (iii) alkoxy, (iv) aryl, (v) cycloalkyl, (vi) hetcroaryl, (vii) heterocyclyl, (viii) alkoxycarbonyl, (ix) carboxy, and (x) halo;
wherein (i)-(iii) can be optionally substituted with 1-4 substituents independently selected from aryl, alkoxy, cycloalkyl, heteroaryl, heterocyclyl, alkoxycarbonyl, carboxy, and halo; and
wherein (iv)-(vii) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy;
(c) aryl, cycloalkyl, heteroaryl, heterocyclyl;
wherein each group defining (c) can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyalkyl, amino, aminoalkyl, aryl, carboxamido, carboxamidoalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, heteroaryl, heterocyclyl, hydroxy, hydroxyalkyl, hydroxyalkoxy, halo, haloalkyl, nitro, perfluoroalkyl, and perfluoroalkoxy.
In another embodiment, the present invention is directed to methods of selectively modulating the antagonism effects of the glucocorticoid receptor in a mammal comprising administering a therapeutically effective amount of a compound of formula I.
In yet another embodiment, the invention is directed to a method of treating diabetes, hyperglycemia, hyperinsulinemia, inadequate glucose clearance, obesity, hypertension, and high glucocorticoid levels, the method comprising administering one or more compounds of formula I.
In yet another embodiment, the invention is directed to pharmaceutical compositions containing compounds of formula I.
The term xe2x80x9calkanoylxe2x80x9d refers to an alkyl group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9calkanyloxyxe2x80x9d refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkenylxe2x80x9d refers to a monovalent straight or branched chain group of two to twelve carbons derived from a hydrocarbon having at least one carbonxe2x80x94carbon double bond. The alkenyl groups of this invention can be optionally substituted with 1-5 substituents selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, substituted heteroaryl, and substituted heterocycle groups are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9calkenyloxyxe2x80x9d refers to an alkenyl group attached to the parent molecular group through an oxygen atom, with the proviso that the double bond is not directly attached to the oxygen atom.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkoxyalkylxe2x80x9d refers to an alkoxy group attached to the parent molecular group through an alkylene group.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d refers to an alkoxy group attached to the parent molecule through an alkoxy group.
The term xe2x80x9calkoxyalkynyl,xe2x80x9d refers to an alkoxy group attached to the parent molecule through an alkynyl group.
The term xe2x80x9calkoxyarylxe2x80x9d refers to an alkoxy group attached to the parent molecule through an aryl group.
The term xe2x80x9calkoxycarbonylxe2x80x9d refers to an ester group, for example, an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d refers to an alkyl group to which is attached at least one alkoxycarbonyl group.
The term xe2x80x9calkoxycarbonylalkenyloxyxe2x80x9d refers to an alkoxycarbonyl group attached to the parent molecule through an alkenyloxy group.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent straight or branched chain group of one to twelve carbons derived from a saturated hydrocarbon. The alkyl groups of this invention can be optionally substituted with 1-5 substituents selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, substituted heteroaryl, and substituted heterocycle groups substituting the alkyl groups of this invention are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9calkyl sulfonamido,xe2x80x9d refers to an alkyl group attached to the parent molecule through a sulfonamido group.
The term xe2x80x9calkylenexe2x80x9d refers to a divalent straight or branched chain group of one to twelve carbons derived from an alkane.
The term xe2x80x9calkenylenexe2x80x9d refers to a divalent straight or branched chain group of one to twelve carbons with at least one double bond.
The term xe2x80x9calkynylxe2x80x9d refers to a monovalent straight or branched chain hydrocarbon of two to twelve carbons with at least one carbonxe2x80x94carbon triple bond. The alkynyl groups of this invention can be optionally substituted with 1-5 substituents selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, substituted heteroaryl, and substituted heterocycle groups substituting the alkyl groups of this invention are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9calkynyloxyxe2x80x9d refers to an alkynyl group attached to the parent molecular group through an oxygen aton, with the proviso that the triple bond is not directly attached to the oxygen atom.
The term xe2x80x9calkanoylaminoxe2x80x9d refers to an alkanoyl group attached to the parent molecule through an amino group.
The term xe2x80x9calkanoylarylxe2x80x9d refers to an alkanoyl group attached to the parent molecule through an aryl group.
The term xe2x80x9calkanoylaryloxyxe2x80x9d refers to an alkanoylary group attached to the parent molecule through an oxy group.
The term xe2x80x9calkanoyloxyalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at least one alkanoyloxy substituent.
The term xe2x80x9calkanoyloxyalkenyl,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, to which is attached at least one alkanoyloxy substituent.
The term xe2x80x9caminoxe2x80x9d refers to xe2x80x94N(R20)(R21) wherein R20 and R21 are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted alkoxyalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, haloalkyl, alkoxyalkyl.
The term xe2x80x9caminoalkylxe2x80x9d refers to an alkyl group, as defind herein, to which is attached at least one amino group.
The term xe2x80x9caminoarylxe2x80x9d refers to an amino group attached to the parent molecule through an aryl group.
The term xe2x80x9carylxe2x80x9d refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of this invention can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, aminosulfonylalkyl, aminosulfonylalkenyl, azido, carboxaldehyde, (carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl, carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl, haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro, oxo, perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, heteroaryl, and heterocycle groups substituting the aryl groups of this invention are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9carylalkylxe2x80x9d refers to an aryl group attached to the parent molecule through an alkyl group.
The term xe2x80x9carylalkenyl,xe2x80x9d refers to an aryl group attached to the parent molecule through an alkenyl group.
The term xe2x80x9carylalkynylxe2x80x9d refers to an aryl group attached to the parent molecule through an alkynyl group.
The term xe2x80x9caryloxyxe2x80x9d refers to an aryl group attached to the parent molecule through an oxygen atom.
The term xe2x80x9carylsulfanamido,xe2x80x9d refers to an aryl group attached to the parent molecule through a sulfonamido group.
The term xe2x80x9ccarboxyxe2x80x9d refers to xe2x80x94CO2H.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at least one carboxy substituent.
The term xe2x80x9ccarboxyaryl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, to which is attached at least one carboxy substituent
The term xe2x80x9ccarboxamidoxe2x80x9d refers to an amino group, as defined herein, attached to the parent molecular group through a C(O) group.
The term xe2x80x9ccarboxamidoalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at least one carboxamido substituent.
The term xe2x80x9ccyanoxe2x80x9d refers to xe2x80x94CN.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at least one cyano substituent.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to a monovalent group derived from a cyclic or bicyclic hydrocarbon of three to twelve carbons that has at least one carbonxe2x80x94carbon double bond.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent group three to twelve carbons derived from a saturated cyclic or bicyclic hydrocarbon. The cycloalkyl groups of this invention can be optionally substituted with 1-5 substituents independently selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, substituted heteroaryl, and substituted heterocycle substituting the cycloalkyl groups of this invention are substituted with 1-5 substituents independently selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to F, Cl, Br, or I.
The term xe2x80x9chaloalkylxe2x80x9d refers to an alkyl group substituted with one or more halogen atoms.
The term xe2x80x9chaloalkylsulfonamidoxe2x80x9d refers to a haloalkyl group attached to the parent molecule through a sulfonamido group.
The term xe2x80x9chaloalkoxyxe2x80x9d refers to a haloalkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9cheterocyclyl,xe2x80x9d as used herein, refers to cyclic, non-aromatic, four-, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur. The four-membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six- and seven-membered rings have zero, one, or two double bonds. Heterocycle groups of the invention are exemplified by dihydropyridinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl, and the like. The heterocycle groups of this invention can be fused to an aryl group or a heteroaryl group. The heterocycle groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen atom in the ring.
Heterocyclyls also include bridged bicyclic groups wherein a monocyclic heterocyclic group is bridged by an alkylene group such as 
and the like.
The heterocycle groups of this invention can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, aminosulfonylalkyl, aminosulfonylalkenyl, azido, carboxallehyde, (carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl, carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl, haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro, oxo, perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, heteroaryl, and heterocycle groups substituting the heterocycle groups of this invention are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to cyclic, aromatic five- and six-membered groups, wherein at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon. The five-membered rings have two double bonds, and the six-membered rings have three double bonds. The heteroaryl groups of the invention are connected to the parent molecular group through a substitutable carbon or nitrogen in the ring. Heteroaryls are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like. The heteroaryl groups of this invention can be fused to an aryl group, a heterocycle, or another heteroaryl. The heteroaryl groups of this invention can be optionally substituted with 1-5 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl, aminosulfonylalkyl, aminosulfonylalkenyl, azido, carboxaldehyde, (carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl, carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl, haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro, oxo, perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl, perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle. The substituted aryl, heteroaryl, and heterocycle substituting the heteroaryl groups of this invention are substituted with at least one substituent selected from alkyl, alkoxy, carboxy, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9c(heteroaryl)heteroarylsulfonamidoxe2x80x9d refers to a heteroarylsubstituted heteroaryl group attached to the parent molecule through a sulfonamido group.
The term xe2x80x9chydroxyxe2x80x9d refers to xe2x80x94OH.
The term xe2x80x9chydroxyalkylxe2x80x9d refers to a hydroxy group attached to the parent molecule through an alkyl group.
The term xe2x80x9chydroxyalkoxyxe2x80x9d refers to an alkoxy group to which ia attached at least one hydroxy group.
The term xe2x80x9chydroxyalkynylxe2x80x9d refers to a hydroxy group attached to the parent molecule through an alkynyl group.
The term xe2x80x9cN-protected aminoxe2x80x9d refers to groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1981)). Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
The term xe2x80x9cO-protected carboxyxe2x80x9d refers to a carboxylic acid protecting ester or amide group typically employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are performed. Carboxy protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (1981). Additionally, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields as described in U.S. Pat. Nos. 3,840,556 and 3,719,667.
The term xe2x80x9coxoxe2x80x9d refers to (xe2x95x90O).
The term xe2x80x9csulfonamido,xe2x80x9d as used herein, refers to sulfonyl group appended to the parent molecular moiety through a amino group.
The term xe2x80x9csulfonylxe2x80x9d refers to an xe2x80x94SO2-group.
The term xe2x80x9ctrialkylsilylalkylxe2x80x9d refers to a trialkyl silyl group attached to the parent molecule through an alkyl group.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term xe2x80x9cprodrugxe2x80x9d represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
Compounds of the present invention can exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbols xe2x80x9cRxe2x80x9d or xe2x80x9cS,xe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and equal mixtures of enantiomers are designated (xc2x1). Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of enantiomers on chiral chromatographic columns.
Geometric isomers can also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbonxe2x80x94carbon double bond or arrangement of substituents around a ring. Substituents around a carbonxe2x80x94carbon double bond are designated as being in the Z or E configuration where the term xe2x80x9cZxe2x80x9d represents substituents on the same side of the carbonxe2x80x94carbon double bond and the term xe2x80x9cExe2x80x9d represents substituents on opposite sides of the carbonxe2x80x94carbon double bond. The arrangement of substituents around a ring are designated as cis or trans where the term xe2x80x9ccisxe2x80x9d represents substituents on the same side of the plane of the ring and the term xe2x80x9ctransxe2x80x9d represents substituents on opposite sides of the plane of the ring. Mixtures of compounds where the substitutients are disposed on both the same and opposite sides of plane of the ring are designated cis/trans.
The present invention also provides pharmaceutical compositions, which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term xe2x80x9cparenteralxe2x80x9d administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Conversely, reduced particle size may maintain biological activity.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposorres or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposoines. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
The compounds of the invention can be prepared by employing reactions shown in the Schemes below. It will be readily apparent to one of ordinary skill in the art that the compounds can be synthesized by substitution of the appropriate reactants in these syntheses, and that the steps themselves can be conducted in varying order. For example, in the schemes below, R2, R3, R4, R6, R7, and R8, whenever convenient, are hydrogen for ease of illustration only. The chemistry employed in the schemes can be conducted when these groups are other than hydrogen. It will also be apparent that protection and deprotection steps can be performed to successfully complete the syntheses of the compounds. A thorough discussion of protecting groups is provided in Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999).
Abbreviations that have been used in the descriptions of the scheme and the examples that follow are: DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide; TPAP for tetra-n-propylammonium perruthenate; and THF for tetrahydrofuran. 
One method for the synthesis of compounds of this invention is described in Scheme I. In this route a derivatized resorcinol dimethyl ether is metallated at the 2-position using a strong base (for example n-butyllithium or s-butyllithium or the like) and transmetallated (for example to provide the organozincate or boronic acid derivative), and is then coupled with an aryl halide (for example in the presence of a palladium (II) catalyst or the like) to provide a biaryl coupling product. Cleavage of the methyl ethers (for example using hydrogen bromide, boron tribromide, TMS-iodide, or the like) leads to lactonization to provide a phenolic product which may be reacted with an alkyl halide (for example methyl iodide or benzyl bromide or the like) in the presence of base to provide the corresponding ether. Reduction of the nitro group (for example, using hydrogen gas and a platinum, palladium, or nickel catalyst, or alternatively using a metal like zinc or iron or the like) provides an aniline which can be reacted with an electrophilic reagent (for example, bromine or n-bromosuccinimide) to derivatize the 7-position. This substituent may optionally be exchanged (for example, using a palladium catalyst and an organometallic reagent like tetramethyltin), after the aniline has been protected (for example as a t-butyl carbamate or the like). Functionalization of the C-6 position may be accomplished through the addition of an organometallic reagent (for example n-butyllithium or phenylmagnesium bromide or the like). the, resultant hemiacetal may be reacted in the presence of a Lewis acid (for example boron trialuoride etherate or trimethylsilyl triflate or the like) with a nucleophile (for example allyltrimethylsilane, tetramethyltin, anisole or the like), or alternatively with a reducing agent like triethylsilane or the like. Conversion to the target compound is accomplished through removal of the aniline protecting group (which may have occurred spontaneously in the previous step) and sequential reaction of the resultant aniline with one or more electrophilic reagents (for example, methyl iodide, propionyl chloride, methanesulfonyl chloride, or the like). 
A specific implementation of this generic route is demonstrated in Scheme II. Resorcinol dimethyl ether is metallated with n-butyllithium at xe2x88x9220xc2x0 C., treated with a trimethylborate and hydrolyzed upon workup with 2M HCl to provide boronic acid 1A. Treatment of 1A with methyl 5-nitro-2-bromobenzoate in the presence of dichloiobis(triphenylphosphine)palladium (II) provides the biaryl coupling product 1B. Demethylation of 1B with BBr3 occurs with spontaneous lactonizationto provide hydroxylactone 1C, which is then treated methyl iodide and cesium carbonate to provide 1D. Conversion of 1D to amine 1E is accomplished using hydrogen gas and a palladium catalyst such as 10% palladium on carbon. Treatment of aniline 1E with N-bromosuccinimide results in regioselective bromination to form 1F, which is protected as its t-butyl carbamate 1G by treatment with triphosgene and t-butyl alcohol. Conversion of 1G to 1H may be accomplished using tetramethyltin in the presence of tetrakis(triphenylphosphine)palladium(0). Introduction of functionalization at the C-6 position is accomplished through addition of 3-trifluoromethylphenylmagnesium bromide to the C-6 carbonyl of 1H to provide 1I, followed by deoxygenation with BF3xe2x88x92OEt3 and triethylsilane to provide the free aniline 1J. Final conversion of 1J to 1 may be accomplished by treatment of aniline 1J with methanesulfonyl chloride to provide sulfonamide 1.
Scheme III demonstrates an alternative synthesis starting from lactone in which the order of the addition and reduction steps are reversed. After protection of the aniline group (for example as a benzyl or tert-butyl carbamate), reduction (for example using sodium borohydride, DIBAL, lithium aluminum hydride, or the like) provides a lactol. Addition of a nucleophile (for example allyltrimethylsilane, phenylmagnesium bromide, anisole, or the like) in the presence of a Lewis acidic catalyst (for example boron trifluoride etherate, zinc chloride, trimethylsilyl triflate, or the like) provides the corresponding cyclic ether, which may be deprotected using trifluoroacetic acid or hydrogenation over a palladium or platinum catalyst or the like) and reacted with a series of electrophilic reagents (for example methanesulfonyl chloride or acetyl chloride or benzyl bromide or the like) to provide the desired analog. Alternatively the nitrogen substituents may be replaced prior to the addition of the C-6 substituent. 
The generic synthesis described above is specifically exemplified in Scheme IV. An intermediate bromoaniline, prepared as described in Schemes I and II, is protected as the corresponding benzyl carbamate through the action of phosgene followed by addition of benzyl alcohol. DIBAL reduction of the lactone provides the corresponding lactol, which is hydrogenated in methanol using 10% palladium-on-carbon to free the aniline. Conversion of the aniline to methanesulfonamide is accomplished using methanesulfonyl chloride in pyridine, and the C-6 allyl group is added using allyltrimethylsilane in the presence of boron trifluoride etherate. 
Alternatively (Scheme V) the addition of the nucleophile may occur after final modification of aniline nitrogen. Thus, removal of the phenolic protecting group results in cyclization to a lactol, which is reacted with a nucleophile under Lewis acidic conditions to provide product. 
In a specific exemplification, the MOM-aldehyde shown in Scheme VI is deprotected with p-toluenesulfonic acid in methanol to provide a lactol methyl acetal. Upon treatment with allyltrimethylsilane in the presence of boron trifluoride etherate, this acetal is converted to the corresponding C6-allyl derivative. 
Yet another route to the compounds of the present invention is described generically in Scheme VII. A substituted phenol is protected (for example, as a methyl ether, trimethylsilyl ether, or methoxymethyl ether or the like), then is metallated and coupled with an aromatic halide as described in Scheme I. After reduction and derivatization of the nitro group as described previously, the B-ring carbonyl group is modified to provide an aldehyde or ketone (for example, through reduction using DIBAL and oxidation using TPAP arid N-methylmorpholine oxide to generate an aldehyde, or addition of an organometallic reagent like phenyllithium to generate a ketone). Addition of an organometallic reagent (for example, n-butyllithium, or 3-allyloxyphenylmagnesium bromide, or the like) produces an alcohol. After deprotection (for example, using HBr in acetic acid, or aqueous or alcoholic HCl, or trimethylsilyliodide, or the like) the resultant phenol is cyclized to produce the desired analog under acidic conditions (for example, upon treatment with p-toluenesulfonic acid in toluene, or boron trifluoride etherate, or trimethylsilyl triflate, or the like). 
Scheme VIII demonstrates a specific synthesis according to Scheme VII. 3-Methoxyphenol is converted to its methoxyethyl ether through treatment with MOM-Cl in the presence of sodium or cesium carbonate. Metallation with n-butyllithium at low temperature, followed by transmetallation with zinc chloride and palladium-mediated coupling with methyl 2-bromo-4-nitrobenzoate, provides the biaryl derivative. The nitro group is reduced using hydrogen gas in the presence of a 10% palladium-on-carbon catalyst and sulfonylated using methanesulfonyl chloride in pyridine; the ester is reduced to an alcohol with DIBAL and oxidized back to the aldehyde using tetrapropyl ammonium perruthenate (TPAP) with N-methylmorpholine as cooxidant. Addition of 3-methoxyethoxyphenyllithium provides an alcohol which may be cyclized by treatment with HCl in methanol to provide the desired analog. 
Compounds of the present invention may also be prepared through modification of other compounds of the present invention. Thus, as shown in Scheme IX, the phenol derivative may be reacted with trifluoromethansulfonic anhydride to produce a phenyl triflate, which may be coupled with a variety of nucleophiles under palladium catalysis. One example is tributyltin-cyanide, which produces the corresponding nitrile derivative.
The invention will now be described in connection with preferred embodiments of the Schemes, which are not intended to limit its scope. On the contrary, the invention covers all alternatives, modifications, and equivalents which are included within the scope of the claims. Thus, the following examples show an especially preferred practice of the invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.